The purpose of the proposed SBIR Phase 1 feasibility study is to assess the efficacy of our lead tumor necrosis factor- alpha (TNF1) inhibitor for the treatment of obesity. Two-thirds of U.S. adults are obese or overweight according to NIH statistics published in 2006. In addition to increased mortality observed in obesity, it is estimated that 70% of cardiovascular disease and 80% of type II diabetes is directly related to obesity. Thus, oral anti-obesity treatments have tremendous clinical significance. Several lines of recent evidence suggest that chronic low-grade inflammation fueled by adipose tissue-derived TNF1 is an underlying cause of obesity and obesity- related insulin resistance. Studies in human obesity and animal models of obesity strongly implicate TNF1 as target that can be modulated to treat obesity and improve obesity-related disorders. P2D, Inc. is developing small molecule TNF1 inhibitors that are amenable to oral administration to treat obesity and obesity-related insulin resistance. Our Preliminary Studies demonstrate that our lead compound did not elicit any taste aversion. Further, daily oral administration triggered significant weight loss in rats without causing any visceral illness. Our Specific Aims for the proposed studies will confirm and extend these observations employing a diet induced rat model of obesity: Specific Aim 1. To determine whether our lead TNF1 inhibitor results in a conditioned taste aversion across a wide dose range. Specific Aim 2a: To determine the dose-dependent effect of our lead TNF1 inhibitor on food intake, body weight, energy expenditure, circadian activity, and total body fat/lean body mass in high-fat diet-induced obese rats and lean rats fed standard low-fat lab chow. Aim 2b: To determine the effects of diet and our lead TNF1 inhibitor on adipose tissue and muscle TNF1 mRNA and protein levels, and obesity-related co-morbidities such as insulin sensitivity and glucose tolerance. PUBLIC HEALTH RELEVANCE: Obesity is a significant health problem in the U.S. Obesity is a chronic inflammatory condition characterized by elevated levels of inflammation within the fat tissue. The present research aims to develop orally-active compounds that target obesity-associated inflammation to trigger weight loss and improve obesity-related insulin resistance.